Representative examples of drugs introduced in anti-tumoral chemotherapy are: cis-diamine-dichloroplatinum, also referred to as CDDP or cis-platinum, cyclophosphamide, 5-fluorouracyl, doxorubicin (adriamycin), metaxanthrone, methotrexate, etoposide, vincristine and bleomycin; each being characterized by different mechanisms of action and by different schedules of administration.
Few cancer chemotherapeutic agents are effective as single agents; most of them are often used in combination with other anti-tumoral agents so employing a variety of different mechanisms to kill malignant cells.
Polychemotherapeutic antitumoral regimens are particularly preferred for management of those tumoral forms that are refractory to a single agent (as it often happens in certain cases of solid tumors), with the aim of obtaining the highest possible index of remission of the disease and of preventing the onset of resistance to a single chemotherapeutic agent.
Each cancer chemotherapeutic agent unfortunately induces side-effects and toxicity that are often so serious to prevent the continuation of therapy, thus precluding the final success of therapeutical schemes. Combined use of anti-tumoral agents, according to the usual practice of chemotherapy, causes even more the cumulative onset of all side-effects of the single compounds.
For instance, the side-effects pattern become more serious when two or more of these compounds are used in combination or together with other anthracycline (e.g., adriamycin) or anthraquinone compounds, that have myocardiotoxicity as the most serious additional side-effect.
An attempt to improve the therapeutic possibilities in the treatment of tumors, is accomplished either by finding out new and more active agents, with a minor toxicity (see for example the new cis-platinum complexes, e.g. compounds known s NSC 311056, NSC 241240 and NSC 256927, widely experimented), or in a more immediate way by increasing the therapeutic index of compounds already available by means of treatments to be carried out simultaneously with antineoplastic agents. Up to now, the latter approach has been mainly used in order to correct and limit the side-effects inseparable from the anti-neoplastic therapy itself.
So, for example, in order to limit the dose-dependent nephrotoxic effect induced by cis-platinum in 80-90% of cases, with noticeable tubular damages shown by the increase of urinary levels of N-acetylglucosaminidase (NAG) and of alanine-aminopeptidase (AAP), the patients are subjected to a forced-hydration regimen by means of prolonged intravenous infusions with saline, glucose or mannitol solutions.
Said protective treatment, which is anyhow quite uncomfortable for the patient, is necessary, but turns out to be sometimes insufficient, especially in those cases when administration of large quantities of platinum complexes is required.
Moreover, the same protective treatment could be dangerous in case of renal insufficiency and/or in the presence of cardiovascular diseases, as a consequence of the great amounts of the fluids which are necessarily administered.
Thus, for example, prevention of toxic damages, particularly urotoxicity, induced by cytostatic oxazaphosphorinic agents is pursued by concomitant administration of mercapto-alkane-sulphonic acids as disclosed by EP No. 2495.
Otherwise, animal experiments seem to suggest that prevent and sequential administration of a natural thiol compound such as reduced glutathione (.alpha.-glutamyl-glycinyl-cysteine) could be useful for preventing renal-and urotoxicity induced by both the anti-tumoral agents: cyclophosphamide and cis-platinum (see for example Tumori 69. 105 (1983) and cancer, Chemother., Pharmac. 14, 188, 1985). Unfortunately, the extremely high dosages of GSH (from 200 mg/kg up to 4 g/kg in divided doses) used in said experimental studies for achieving some beneficial effects rules out any real utility of this natural thiol in the clinical practice.
Useful doses in men would require the administration of 15-280 g administration of 15-280 g of GSH, adding serious practical problems to those already perceived during hydration regimen.
Current knowledges (ride infra), looking at the lowering of intracellular GSH level as a therapeutical aim to be pursued in order to favour antineoplastic therapy, furtherly discourages this approach.
On the contrary, reduced GSH has been recently proposed as effective and clinically useful protecting agent in men towards side-effects (particularly tubular damages) of platinum complexes and particularly "cis-platinum", (Italian patent application No. 20591 A/85 of 6th May, 1985) when administered in a dose range from 2.5 to 5 g as total dose for each side-effects preventive treatment by infusional route.
Said treatment, not changing the hydration regimen, is claimed to limit tubular damages, as shown by NAG and AAP enzymes determination in urine, without significant detrimental effects on anti-tumor activity.
All these known treatments do not allow however the increase of administration dosages of anti-tumoral compounds to the level that should be necessary in particular conditions of natural or induced resistance (for example in most cases of solid tumors, in particular those of the lungs and colon).
A great effort has been recently made to find substances which are able to restore the sensitivity of resistant cells to drugs such as doxorubicin, vincristine, cis-platinum, and which can possibly increase the cytotoxicity.
So, for example, calmodulin, an ubiquitous calcium-binding protein, responsible for many of the intracellular actions of calcium, was recently proposed as a potential target for cancer chemotherapeutic agents, (W. H. Hait J. of Clin. Oncol. 4, 994 (1986). Some calmodulin antagonists are themselves cytotoxic substances and various trials are running to prove if their inclusion in traditional cytotoxic chemotherapeutic regimens may extend the efficacy of the currently available drugs.
Recent studies have also concentrated on the use of calcium channel blockers in combination with classical cancer chemotherapeutic agents.
On the other hand, the use of buthionine sulphoximine as a specific agent for depletion of GSH from cells has been proposed by Andrews et al. in Cancer Res. 45, 6250, 1985 to enhance the cyto-toxic activity of compounds such as L-phenylalanine mustard, chlorambucyl, CDDP, mechlorethamine, carboplatin, diclorethylendiamine-platinum (II), 1,2-diamino-cyclohexyl platinum [II]-malonate.